Surface layers of Gram-negative bacteria are composed of cell membranes, cell wall peptide glucan surrounding the membrane, and outer membranes. The outer membrane contains lipopolysaccharide (hereinafter abbreviated LPS). LPS is a main ingredient of endotoxin which induces endotoxin shock, and consists of an acidic protein component, a high molecular polysaccharide component, and a phospholipid component.
LPS shows such functions as causing pyretogenesis, hemorrhage, arthritis, and encephalomyelitis. Moreover, LPS has been known to show immunopotentiating effect of a host-protecting mechanism such as macrophage activation, B cell blastogenesis, and cell-mediated immunity activation, as well as anti-tumor effect such as interferon induction, and TNF induction.
LPS expresses its activity mainly by the phospholipid part called lipid A among said three components. Lipid A comprises fatty acid residue and phosphoric acid both of which are combined with disaccharide amine, and has the following formula (Japanese Bacteriology Journal 40(1), 57(1985); Proc. Natl. Acad. Sci. USA. 80,4626 (1983)). ##STR2##
Recent study has revealed that either a nonreducing subunit or a reducing subunit as shown above alone is able to show lipid A-like activity. Based on this finding, various analogues have been synthesized concerning lipid A.
For example, Japanese Patent Disclosure No. 501259/85 discloses lipid A analogues which closely approximate to the reducing subunit and a method for producing the analogues. Japanese Patent Disclosure No. 146891/89 discloses monophosphoryl lipid A derivatives. Also, Japanese Patent Disclosure No. 246195/86 discloses novel disaccharide and trisaccharide derivatives of lipid A type. Japanese Patent Disclosure No. 275299/86 discloses deoxymuramyldipeptide derivatives. Further, Japanese Patent Disclosure Nos. 52793/89 and 179885/88 disclose glucopyranose derivatives obtained by converting a phosphoric acid residue of the non-reducing subunit in lipid A into sulphuric acid residue.
Inventors of the present invention have made extensive investigation in order to synthesize lipid A derivatives which show a stronger immunomodulating activity. Specifically, by changing substituents or substitutent-sites of a non-reducing subunit, many derivatives were synthesized. As a consequence, some of the derivatives synthesized as said have been found to show a strong immunopharmacological activity, and patent applications for them have already been filed (e.g., Japanese Patent Application Nos. 215613/88, 215612/88, and 172918/88, and Japanese Patent Disclosure Nos. 146892/89, 44588/88, 33391/88, 30495/88, 129292/87, 172867/86, 126094/86, and 126093/86).
As described above, extensive studies have been conducted in order to obtain lipid A analogues, specifically by modifying them with various substituents and by changing substituent sites introduced. However, such a problem has not yet overcome as obtaining different activities for different introduction sites of the same substituents, and thus lipid A analogues have not yet been developed which are applicable as pharmaceutical agents. Therefore compounds showing a more effective lipid A-like activity are earnestly expected to be developed.